Systems and methods for driving sealed nebulizers

ABSTRACT

Various methods, devices, and systems are described for aerosolizing a liquid. Embodiments may include sealing the liquid within a reservoir. An output waveform signal may be generated. A nebulizer element may be vibrated to aerosolize the liquid. A negative pressure may be produced within the reservoir as the liquid is aerosolized. The output waveform signal may cause the nebulizer element to vibrate. Embodiments may involve determining a phase shift between a current of the output waveform signal and a voltage of the output waveform signal. Also, embodiments may involve adjusting a frequency of the output waveform signal at least partially based on the phase shift. Further, embodiments may involve adjusting the voltage of the output waveform signal at least partially based on the frequency of the output waveform signal.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/384,579, filed Jan. 17, 2012, which is a National Stage Entry ofPCT/US2010/042473 filed Jul. 19, 2010 and claims the benefit of U.S.Provisional Patent Application No. 61/226,591, filed Jul. 17, 2009entitled SYSTEMS AND METHODS FOR DRIVING SEALED NEBULIZERS, and isrelated to co-pending Provisional Patent Application No. 61/226,567,filed Jul. 17, 2009 entitled NEGATIVELY BIASED SEALED NEBULIZERS SYSTEMSAND METHODS, the entire disclosures of which is incorporated byreference for all purposes.

BACKGROUND OF THE INVENTION

Embodiments of the present invention relate to nebulizers. Inparticular, the present invention relates to use of a variable voltageand frequency driver for a nebulizer having a sealed liquid drugreservoir capable of maintaining a negative internal bias pressure.

A wide variety of procedures have been proposed to deliver a drug to apatient. In some drug delivery procedures the drug is a liquid and isdispensed in the form of fine liquid droplets for inhalation by apatient. A patient may inhale the drug for absorption through lungtissue. Further, the droplets forming the atomized mist may need to bevery small to travel through small airways of the lungs. Such a mist maybe formed by a nebulizer.

SUMMARY

Various systems, methods, and devices are described for driving anebulizer using a driver unit. The nebulizer may include a sealed drugreservoir such that a negative bias pressure may form within the drugreservoir as liquid is drained from it. As the negative bias pressurechanges, the resonant frequency of the nebulizer element may change. Adriver may be used to drive the nebulizer element and cause it tovibrate. The driver may output a waveform signal of varying frequencyand magnitude to the nebulizer such that the nebulizer element vibratesat or near a resonant frequency and the nebulizer element atomizesliquid at a constant or near constant rate and droplet size.

In some embodiments, a method for determining a resonant frequency of anelement of a nebulizer with a negatively biased liquid reservoir isdescribed. The method may include driving a nebulizer using anelectrical signal, the electrical signal comprising a current and avoltage. The method may include measuring a phase shift between thevoltage and the current of the electrical signal driving the nebulizer.The method may also include, based at least in part on the phase shiftof the electrical signal driving the nebulizer, determining, a resonantfrequency of the element of the nebulizer.

In some embodiments, the method further comprises based at least in parton the resonant frequency of the nebulizer determined by the driver,determining, a voltage magnitude for the electrical signal. In someembodiments, the negatively biased liquid reservoir causes the resonantfrequency of the element of the nebulizer to vary as liquid is drainedfrom the negatively biased liquid reservoir. In some embodiments, theelectrical signal driving the nebulizer causes the element of thenebulizer to vibrate and atomize liquid stored in the negatively biasedliquid reservoir. In some embodiments, the method further comprisesbased at least in part on the resonant frequency of the nebulizerdetermined by the driver, determining, by the driver, a negative biaspressure within the negatively biased liquid reservoir of the nebulizer.In some embodiments, the method further comprises adjusting thefrequency of the electrical signal to the nebulizer, wherein a roughlyconstant phase shift is maintained between the voltage and current ofthe electrical signal. In some embodiments, the voltage magnitude isdetermined using a stored set of values, and the stored set of valuesvary depending on a liquid in the negatively biased liquid reservoir.

In some embodiments, a device for driving an element of a nebulizer ispresent. The device may include an amplifier, configured to generate anoutput waveform signal, the output waveform signal comprising an outputcurrent and an output voltage, wherein the output waveform signal drivesthe element of the nebulizer at the output frequency. The device mayinclude a phase shift detector, configured to determine the phase shiftbetween the output current and the output voltage of the output waveformsignal. The device may include a resonant frequency tracker, configuredto generate a waveform signal of a variable frequency input to theamplifier, wherein the variable frequency is adjusted based on the phaseshift of the output waveform signal determined by the phase shiftdetector module. The device may include a voltage profile, configured toadjust the output voltage of the output waveform signal output by theamplifier based on the frequency of the waveform signal generated by theresonant frequency tracker.

In some embodiments, a system for atomizing liquid stored in anegatively bias pressured liquid reservoir may be present. The systemmay include a nebulizer, comprising an element and the negatively biaspressured liquid reservoir. The element may be configured to vibrate toatomize liquid drained from the negatively bias pressured liquidreservoir. A negative bias pressure of the negatively bias pressuredreservoir may change as liquid stored in the negatively bias pressuredliquid reservoir is drained. The negatively bias pressured reservoir maybe sealed such that air from the external environment substantially doesnot enter the negatively bias pressured reservoir as liquid stored inthe negatively bias pressured liquid reservoir is drained. The systemmay include a driver. The driver may include a phase shift detector,configured to determine the phase shift between a current of an outputwaveform signal and a voltage of the output waveform signal. The drivermay include a resonant frequency tracker, configured to generate anoutput waveform that adjusts the frequency of the output waveformsignal, wherein the frequency is adjusted based on the phase shiftdetermined by the phase shift detector module. The driver may include avoltage profile, configured to adjust a voltage of the output waveformsignal based on the frequency of the output waveform generated by theresonant frequency tracker.

In some embodiments, a method for aerosolizing a liquid is present. Themethod may include sealing the liquid within a reservoir. The method mayalso include generating an output waveform signal and vibrating anebulizer element to aerosolize the liquid. A negative pressure may beproduced within the reservoir as the liquid is aerosolized. The outputwaveform signal may cause the nebulizer element to vibrate. The methodmay include determining a phase shift between a current of the outputwaveform signal and a voltage of the output waveform signal. The methodmay include adjusting a frequency of the output waveform signal at leastpartially based on the phase shift. Further, the method may includeadjusting the voltage of the output waveform signal at least partiallybased on the frequency of the output waveform signal.

BRIEF DESCRIPTION OF THE DRAWINGS

A further understanding of the nature and advantages of the presentinvention may be realized by reference to the following drawings. In theappended figures, similar components or features may have the samereference label. Further, various components of the same type may bedistinguished by following the reference label by a second label thatdistinguishes among the similar components. If only the first referencelabel is used in the specification, the description is applicable to anyone of the similar components having the same first reference labelirrespective of the second reference label.

FIG. 1A illustrates a simplified embodiment of a nebulizer.

FIG. 1B illustrates a simplified embodiment of a nebulizer with a driverunit.

FIG. 1C illustrates a simplified embodiment of a handheld nebulizer withan integrated driver unit.

FIG. 1D illustrates a nebulizer integrated with a ventilator.

FIG. 2 illustrates a simplified embodiment of a driver coupled with anebulizer.

FIG. 3 illustrates a method of driving a nebulizer with a driver.

FIG. 4 illustrates a method of initially determining a resonantfrequency of a nebulizer element.

FIG. 5 illustrates a simplified method of adjusting the frequency outputby a driver using a resonant frequency tracker to maintain the nebulizerelement vibrating at its current resonant frequency

DETAILED DESCRIPTION OF THE INVENTION

Devices, systems, and methods are described for the implementation of anovel architecture for driving a nebulizer. The invention providesvarious ways for driving nebulizers at the nebulizers' resonancefrequencies, particularly nebulizers with sealed drug reservoirs capableof developing a negative bias pressure (meaning the pressure within thereservoir is less than the pressure outside of the reservoir) as liquidis evacuated from the drug reservoir.

By creating a negative bias pressure within the drug reservoir of anebulizer, the efficiency of a nebulizer may be increased, thus allowingit to achieve higher liquid flow rates, with smaller and more consistentdroplet sizes, than in comparable conditions without a negative biaspressure. Such a negative bias pressure may be created by sealing thedrug reservoir. As the liquid drug is drained from the drug reservoir(with little to no air entering to replace the drug's volume), anegative bias pressure may be created. While the negative bias pressuremay assist in maintaining consistently sized droplets of mist, as thenegative bias pressure decreases in pressure, the flow rate of liquidfrom the nebulizer may increase.

An increased flow rate caused by a negative bias pressure may lead tothe wrong dose of a medicine being delivered to a patient and/or thegeneration of improper droplet sizes. Such improper droplet sizes mayalter how the droplets are absorbed into the human body. For example, ifa patient inhales droplets that are too large, the droplets may notpropagate into the deep lung tissue of the patient, but rather, thedroplets may gather in the patient's larger airways. This may preventproper absorption of the droplets by the patient.

The droplets may be created from a stored amount of liquid in the drugreservoir by a nebulizer element. The nebulizer element may be anaperture plate containing a number of small holes. When an electricalsignal, such as a waveform, is applied to the nebulizer element, thenebulizer element may vibrate at or near the frequency of the waveformreceived. While vibrating, the nebulizer element may allow an amount ofthe liquid to pass through the element and form airborne droplets. Thenebulizer element may function more efficiently and produce consistentdroplet sizes when the nebulizer element is vibrating at or near itsresonant frequency.

However, as the negative bias pressure within the drug reservoir changes(e.g., a greater difference between the pressure inside the drugreservoir and the ambient pressure outside of the drug reservoir isformed) the resonant frequency of the nebulizer element may change. Inorder to maintain the nebulizer element vibrating at its (current)resonant frequency, it may be necessary to change the frequency ofwaveform used to drive the nebulizer element.

Therefore, if a negative bias pressure is maintained in the drugreservoir, the frequency and magnitude of the waveform used to drive thenebulizer element needs to vary as the negative bias pressure within thedrug reservoir changes in order to maintain efficient operation of thenebulizer element, including maintaining consistent dosing of the liquiddrug and consistent droplet sizes.

To be clear, a sealed reservoir refers to a reservoir that prevents airfrom entering the reservoir as liquid is drained from the drugreservoir. It may, however, still be possible for air to enter thesealed drug reservoir through holes in the nebulizer element. Thegreater the negative bias pressure (that is, the greater the differencebetween the pressure of the external environment and the pressure withinthe drug reservoir) the faster air may enter through the nebulizerelement.

FIG. 1A illustrates an embodiment of a possible nebulizer 100-a. Thenebulizer 100-a may include a nebulizer element 110, a drug reservoir120, a head space 130, an interface 140, and a cap 150. The nebulizerelement 110 may be comprised of a piezoelectric ring that may expand andcontract when an electric voltage is applied to the ring. The nebulizerelement 110 may be a vibrating aperture plate. The piezoelectric ringmay be attached to a perforated membrane. Such a perforated membrane mayhave a number of holes passing through it. When an electric voltage isapplied to the piezoelectric ring, this may cause the membrane to moveand/or flex. Such movement of the membrane, while in contact with aliquid may cause the atomization (alternatively referred to asaerosolization) of the liquid.

A supply of a liquid, commonly a liquid drug, may be held in the drugreservoir 120. As illustrated, a drug reservoir is partially filled witha liquid drug. As the liquid drug is atomized, the amount of liquid drugremaining in the drug reservoir 120 may decrease. Depending on theamount of liquid drug in the drug reservoir 120, only a portion of thereservoir may be filled with liquid drug. The remaining portion of thedrug reservoir 120 may be filled with gas, such as air. This space iscommonly referred to as head space 130. An interface 140 may serve totransfer amounts of liquid drug between the drug reservoir 120 and thenebulizer element 110.

Nebulizers, and the techniques associated with such nebulizers, aredescribed generally in U.S. Pat. Nos. 5,164,740; 5,938,117; 5,586,550;5,758,637; 6,014,970; 6,085,740; 6,235,177; 6,615,824; 7,322,349 thecomplete disclosures of which are incorporated by reference for allpurposes.

A nebulizer with a sealed drug reservoir may be part of a larger system.The embodiment of FIG. 1B illustrates such a system 100-b. FIG. 1Billustrates a nebulizer 151 with a sealed drug reservoir connected to adriver 152. The sealed nebulizer illustrated in FIG. 1B may be thenebulizer of FIG. 1A, or may represent some other nebulizer. Driver 152may control the rate and magnitude of vibration of the nebulizer elementon nebulizer 151. Driver 152 may be connected to nebulizer element 151via cable 153. Driver 152 may regulate the voltage and frequency of thesignal provided to the nebulizer element of nebulizer 151. Theregulation of the voltage and frequency of the signal may be based onthe resonant frequency of the nebulizer element of nebulizer 151. Such asignal may vary depending on the magnitude of the negative biaspressure.

In some other embodiments of nebulizers, a driver may be incorporatedinto a handheld unit with the nebulizer. Nebulizer 100-c of FIG. 1Cillustrates an embodiment of a handheld nebulizer with an integrateddriver. Nebulizer 100-c may include a case 155, a mouthpiece 160, atrigger button 165, and an electrical plug 170. Case 155 may containsome or all of the elements found in other embodiments of nebulizers(such as nebulizer 100-a of FIG. 1A) and drivers (such as driver 152 ofFIG. 1B). Therefore, contained within case 155 may be a sealed drugreservoir and/or a device capable of generating an electrical signal ata voltage magnitude and frequency to vibrate an element that atomizesliquid stored in the drug reservoir. A person receiving the atomizedliquid drug may place her mouth on mouthpiece 160 and breath in. Whilethe person receiving the atomized liquid drug is breathing in, she maypress trigger button 165 to trigger the element to begin aerosolizingliquid. In some embodiments, nebulizer 100-c may contain a sensor thatdetects when the person is breathing in and triggers the element tovibrate without trigger button 165 being necessary.

Nebulizer 100-c may also include an electrical plug 170. Electrical plug170 may be connected to an electrical outlet to power nebulizer 100-c.Nebulizer 100-c may contain a battery, thereby allowing electrical plug170 to be connected to an electrical outlet when nebulizer 100-c is notin use by a person, allowing a battery to be charged. Alternatively, insome embodiments of nebulizer 100-c, electrical plug 170 may need to beconnected to an electrical outlet while nebulizer 100-c is in use by aperson. In some embodiments, nebulizer 100-c may use replaceablebatteries as its power source.

In some embodiments, a nebulizer may operate in conjunction with aventilator. System 100-d illustrates a nebulizer 178 that suppliesatomized liquid drug to a person 176 via a ventilator 170. Ventilator170 may supply air suitable for breathing to person 176. Ventilator 170may assist person 176 in breathing by forcing air into the lungs ofperson 176 and then releasing air to mimic breathing. While person 176is using ventilator 170, it may be necessary to provide person 176 withatomized liquid, such as a liquid drug.

Nebulizer 178 may be connected to a drug reservoir 186 that is sealed bya cap 180. Drug reservoir 186 may contain an amount of liquid drug 182.This liquid drug may be delivered to nebulizer 178 as liquid drug isatomized by nebulizer 178. As liquid drug is atomized, liquid drug 182may drain from drug reservoir 186, thereby increasing the volume ofheadspace 184. Headspace 184 may contain air. Headspace 184 may increasein volume, but may decrease in pressure as liquid drug 182 drainsbecause liquid reservoir 186 allows no or minimal air into headspace184.

Driver 172, which may represent the same driver as driver 152 of FIG. 1B(or may represent some other driver) may deliver a signal to nebulizer178. This signal may control the vibration of an element of nebulizer178. Nebulizer 178 may be attached to a tube 179 used to deliver air andatomized liquid drug to patient 176. Tube 179 may terminate in a mask174 covering the mouth and/or nose of person 176. The air and atomizedliquid drug may then enter the airways of person 176.

A nebulizer such as those illustrated in FIGS. 1A-1D may be connectedwith a driver such as illustrated in FIG. 2. FIG. 2 illustrates asimplified block diagram of a nebulizer driver unit 200. The nebulizer260 may be the nebulizer 100-a of FIG. 1A or it may be some othernebulizer such as those in the referenced applications or FIGS. 1B-1D.The nebulizer may be connected to the driver via a cable 270. Driver 210may be driver 151 of FIG. 1B, or may be some other driver. Cable 270 mayallow driver 210 to transmit an electrical waveform signal of varyingfrequency and magnitude (of voltage) through cable 270 to drivenebulizer 260.

Driver 210 may include an amplifier 230, a current phase shift detector240, a resonant frequency tracker 220, and a voltage profile 250. Basedupon the phase shift between the current supplied to nebulizer 260 andthe voltage generated by amplifier 230, the nebulizer element's resonantfrequency may be determined. From the resonant frequency, the negativebias pressure within the drug reservoir of the nebulizer may bedetermined, and the frequency and/or magnitude of the electricalwaveform signal driving nebulizer 260 may be adjusted.

The determination of the resonant frequency may be accomplished usingcurrent phase shift detector 240. Current phase shift detector 240monitors the phase shift between the phase of the current output byamplifier 230 to nebulizer 260 and the phase of the voltage output byamplifier 230 to nebulizer 260. Based upon the phase shift between thevoltage and current observed by current phase shift detector 240,resonant frequency tracker 220 outputs an output waveform to amplifier230 such that amplifier 230 outputs an electrical waveform signal withconstant or near constant phase shift between the voltage and current ofthe electrical waveform signal driving the element of nebulizer 260.

As liquid is atomized and the bias pressure in the drug reservoirchanges, the resonant frequency may change. Further, factors besides thebias pressure within the sealed drug reservoir of the nebulizer 260 maychange the nebulizer element's resonant frequency. For example, thetemperature of the nebulizer element, excess liquid on the nebulizerelement, and/or damage to the nebulizer element may cause a variation inthe nebulizer element's resonant frequency. However, it may be generallyaccepted that during operation, changes in the nebulizer element'sresonant frequency is generally due to variations in the bias pressurewithin the drug reservoir of the nebulizer.

The resonant frequency and/or the measured change in resonant frequencymay be transmitted to voltage profile 250 by resonant frequency tracker220. Voltage profile 250 may be used to determine the proper magnitudeof voltage to apply to the nebulizer element at a particular resonantfrequency to maintain consistent droplet size and dosing of the atomizedliquid. In some embodiments, voltage profile 250 may include a table ofempirically gathered data. In such embodiments, the resonant frequencymay be located in the table, with a corresponding analog or digitalsignal being output to amplifier 230 that specifies the appropriatemagnitude of voltage amplifier 230 should output. For example, a tablemay include a predetermined voltage magnitude that may be communicatedto amplifier 230 when a particular resonant frequency is measured byresonant frequency tracker module 220. Voltage profile 250 may also beexpressed as a graph of values, with the x-axis being frequency of thewaveform generated by resonant frequency tracker 220, and the y-axisrepresenting the appropriate voltage magnitude to be supplied toamplifier 230 such that amplifier 230 outputs an electrical signal ofcorrect magnitude.

A rough description of one set of possible values for voltage profile250 is that as the resonant frequency of the nebulizer elementincreases, the desired amplitude of the electrical signal output to thenebulizer will decrease. At a certain threshold, as the resonantfrequency continues to increase, the voltage will be held by voltageprofile 250 at a minimum level. In some embodiments of voltage profile250, the signal output to amplifier 230 are determined based on acalculation using the resonant frequency supplied by resonant frequencytracker 220.

The voltage profile may need to be modified or adjusted to accommodatethe characteristics (such as surface tension) of different liquidswithin the drug reservoir of the nebulizer. In some embodiments, aliquid drug, such as Amikasin, is used. In other embodiments, adifferent liquid drug or liquid is used. In some embodiments, thevoltage profiles necessary for a number of liquids or liquid drugs maybe similar enough that only one voltage profile needs to be used formultiple liquids or liquid drugs. Modifying or replacing voltage profile250 may involve selecting a different liquid via a user interface ondriver 210 or loading different software, firmware, and/or hardware intodriver 210.

Resonant frequency tracker 220 may transmit a waveform at or near thenebulizer element's current determined resonant frequency to amplifier230. Voltage profile 250 may transmit a signal indicating the desiredvoltage amplitude to be output by amplifier 230 to amplifier 230. Thissignal from voltage profile 250 may serve to control the gain of theamplifier 230. Based upon the input waveform from resonant frequencytracker 220 and the desired voltage amplitude received from voltageprofile 250, amplifier 230 generates an output electrical signal thatmay be used to drive an aperture of the nebulizer. Amplifier 230 may bea variable gain linear power amplifier. In some embodiments, a fixedgain power amplifier may be used in conjunction with a variable gainamplifier or a potentiometer. Further, various other amplifiers oramplifier based circuits may be used to generate the output electricalsignal to drive nebulizer 260.

Current phase shift detector 240 may create a feedback loop to resonantfrequency tracker 220. Current phase shift detector 240 may determinethe phase shift of the current being output from the amplifier 230. Sucha phase shift may be transmitted to resonant frequency tracker 220,thereby allowing resonant frequency tracker 220 to either maintain thesame frequency signal (if the phase has not shifted), increase thefrequency, or decrease the frequency of the output signal in response tothe resonant frequency of the nebulizer element changing as the biaspressure within the seal drug reservoir changes. Feedback throughcurrent phase shift detector 240 may allow driver 210 to periodically orcontinually adjust the magnitude and frequency of the electrical signaloutput to the nebulizer element while liquid is being atomized. This mayallow for any change in the bias pressure in the liquid reservoir to becontinually adjusted for by the driver.

A driver, such as driver 210 of FIG. 2, may drive a nebulizer elementaccording to a method, such as method 300 of FIG. 3. Alternatively,method 300 may be performed using some other driver. Method 300 mayemploy various different nebulizers, such as the nebulizers of FIGS.1A-1D, and FIG. 2. At block 310, the driver may drive an element (alsoreferred to as an aperture) of a nebulizer with an electrical signal.This electrical signal may be a waveform at a particular frequency andmagnitude.

At block 320, the phase shift between the voltage of the electricalsignal output to the nebulizer and the current of the electrical signalmay be measured. Using this phase shift, at block 330, the resonantfrequency of the nebulizer element may be determined. As previouslynoted, this resonant frequency may shift as the negative bias pressurewithin the liquid reservoir of the nebulizer changes. From the resonantfrequency, the bias pressure within the liquid reservoir may bedetermined at block 340. In some embodiments, the negative bias pressureis not determined.

At block 350, the magnitude of the voltage of the electrical signal usedto drive the nebulizer element may be determined. The magnitude may bedetermined using the resonant frequency determined at block 330 and/orthe negative bias pressure determined at block 340. The resonantfrequency and/or the negative bias pressure may be used to consult atable of values. This table of values may specify the appropriatemagnitude of voltage to be used for the electrical signal driving thenebulizer element. Alternatively, the resonant frequency and/or thenegative bias pressure may be used to calculate the appropriate voltagemagnitude to drive the nebulizer element. The appropriate magnitude maycorrespond to a magnitude that maintains a constant dosage rate anddroplet size of the liquid being dispensed from the nebulizer. Thecalculations or table may vary depending on the properties of the liquidbeing dispensed.

At block 360, the electrical waveform signal driving the nebulizerelement may be adjusted according to the frequency determined at block330 and/or the magnitude determined at block 350. If the resonantfrequency of the nebulizer element has not changed, the frequency and/orthe magnitude of the electrical signal driving the nebulizer element maynot change. Method 300 may repeat as long as the nebulizer element isbeing driven by the driver.

A resonant frequency tracker, such as resonant frequency tracker 220 ofFIG. 2, may follow various methods to determine and maintain an outputat or near the resonant frequency of a nebulizer element, such asnebulizer element 260 of FIG. 2. FIG. 4 illustrates a simplifiedflowchart of a decay profile 400 for initially determining the resonantfrequency of the nebulizer element and adjusting the output electricalsignal driving the nebulizer element based on the phase shift betweenthe voltage and current of the electrical signal driving the nebulizerelement detected by the current phase shift detector. Method 300 of FIG.3 may be implemented using resonant frequency tracker 220 of FIG. 2, ormay be implemented using some other resonant frequency tracker, be itimplemented in software, firmware, and/or hardware.

If the resonant frequency has not been determined or “locked on” to by aresonant frequency tracker, a resonant frequency tracker may conductmethod 400. The resonant frequency tracker may not have locked on to theresonant frequency if, for example, the driver has just been turned onor activated, a new nebulizer is attached to the driver unit, thenebulizer element has been interfered with, or the nebulizer element hasbeen damaged.

At block 411, the resonant frequency tracker may apply an infiniteimpulse response filter (“IIR filter”), to the phase signal receivedfrom the current phase shift detector. The IIR filter may be implementedusing analog and/or digital components. From this, a filtered phasevalue may be obtained.

Using the filter phase value, the error between the filtered phase anddesired phase setpoint may be determined at block 412. The desired phaseset point may indicate the phase necessary to cause the nebulizerelement to vibrate at a resonant frequency. This determined error valuemay then be used to determine if the error has been a smaller value thanthe set point for greater than a second at block 413. In someembodiments, a different length of time is used.

If the error has been less than the set point for more than one second,the current frequency of the signal output to the nebulizer is stored atblock 414. Further, a flag may be set to indicate that the resonantfrequency has been locked on to by the resonant frequency tracker atblock 415. Returning to block 413, if the error has not been less thanthe set point for more than one second, the process proceeds to block430.

At block 430, if the average current is less than some threshold currentvalue, the output voltage may be set to a start voltage at block 432. Atblock 434, the resonant frequency determined by the resonant frequencytracker may be reset to an initial value. If the average current is notless than a threshold current value, blocks 432 and 434 may not beperformed. Method 400 may repeat until the flag indicating the resonantfrequency of the nebulizer element has been locked on to.

Once the resonant frequency has been determined and locked, which mayinvolve the resonant frequency flag of block 414 being set, a secondmethod may be followed. Method 500 represents a method for adjusting thefrequency using a resonant frequency tracker to maintain the nebulizerelement vibrating at its current resonant frequency. The error betweenthe current frequency and resonant frequency may be determined at block521. From this, an error value may be obtained.

A determination of whether the actual frequency of the signal beinggenerated by the resonant frequency tracker is greater than the resonantfrequency of the nebulizer element may be made at block 522. If yes, atblock 523, the output voltage may be scaled by a decay rate multipliedby the error rate determined at block 521, and the output voltage may belimited to the end voltage at block 524. This may prevent the outputvoltage from exceeding some maximum and/or minimum threshold value.Next, the process proceeds to block 530. If the actual frequency is notdetermined to be greater than the resonant frequency at block 522, theoutput voltage is set to a start voltage at block 525, and the methodproceeds to block 530.

At block 530, a determination is made if the current is less than athreshold current value. If so, the output voltage is set to the startvoltage at block 532 and the resonant frequency is reset at block 534.

While a wide variety of drugs, liquids, liquid drugs, and drugsdissolved in liquid may be aerosolized, the following provides extensiveexamples of what may be aerosolized. Additional examples are provided inU.S. application Ser. No. 12/341,780, the entire disclosure of which isincorporated herein for all purposes. Nearly any anti-gram-negative,anti-gram-positive antibiotic, or combinations thereof may be used.Additionally, antibiotics may comprise those having broad spectrumeffectiveness, or mixed spectrum effectiveness. Antifungals, such aspolyene materials, in particular, amphotericin B are also suitable foruse herein. Examples of anti-gram-negative antibiotics or salts thereofinclude, but are not limited to, aminoglycosides or salts thereof.Examples of aminoglycosides or salts thereof include gentamicin,amikacin, kanamycin, streptomycin, neomycin, netilmicin, paramecin,tobramycin, salts thereof, and combinations thereof. For instance,gentamicin sulfate is the sulfate salt, or a mixture of such salts, ofthe antibiotic substances produced by the growth of Micromonosporapurpurea. Gentamicin sulfate, USP, may be obtained from Fujian FukangPharmaceutical Co., LTD, Fuzhou, China. Amikacin is typically suppliedas a sulfate salt, and can be obtained, for example, from Bristol-MyersSquibb. Amikacin may include related substances such as kanamicin.

Examples of anti-gram-positive antibiotics or salts thereof include, butare not limited to, macrolides or salts thereof. Examples of macrolidesor salts thereof include, but are not limited to, erythromycin,clarithromycin, azithromycin, salts thereof, and combinations thereof.For instance, vancomycin hydrochloride is a hydrochloride salt ofvancomycin, an antibiotic produced by certain strains of Amycolatopsisorientalis, previously designated Streptomyces orientalis. Vancomycinhydrochloride is a mixture of related substances consisting principallyof the monohydrochloride of vancomycin B. Like all glycopeptideantibiotics, vancomycin hydrochloride contains a central coreheptapeptide. Vancomycin hydrochloride, USP, may be obtained fromAlpharma, Copenhagen, Denmark.

In some embodiments, the composition comprises an antibiotic and one ormore additional active agents. The additional active agent describedherein includes an agent, drug, or compound, which provides somepharmacologic, often beneficial, effect. This includes foods, foodsupplements, nutrients, drugs, vaccines, vitamins, and other beneficialagents. As used herein, the terms further include any physiologically orpharmacologically active substance that produces a localized or systemiceffect in a patient. An active agent for incorporation in thepharmaceutical formulation described herein may be an inorganic or anorganic compound, including, without limitation, drugs which act on: theperipheral nerves, adrenergic receptors, cholinergic receptors, theskeletal muscles, the cardiovascular system, smooth muscles, the bloodcirculatory system, synoptic sites, neuroeffector junctional sites,endocrine and hormone systems, the immunological system, thereproductive system, the skeletal system, autacoid systems, thealimentary and excretory systems, the histamine system, and the centralnervous system.

Examples of additional active agents include, but are not limited to,anti-inflammatory agents, bronchodilators, and combinations thereof.

Examples of bronchodilators include, but are not limited to, β-agonists,anti-muscarinic agents, and combinations thereof. For instance, thebronchodilator may comprise albuterol, such as albuterol sulfate.

Active agents may comprise, for example, hypnotics and sedatives,psychic energizers, tranquilizers, respiratory drugs, anticonvulsants,muscle relaxants, antiparkinson agents (dopamine antagonists),analgesics, anti-inflammatories, antianxiety drugs (anxiolytics),appetite suppressants, antimigraine agents, muscle contractants,additional anti-infectives (antivirals, antifungals, vaccines)antiarthritics, antimalarials, antiemetics, anepileptics, cytokines,growth factors, anti-cancer agents, antithrombotic agents,antihypertensives, cardiovascular drugs, antiarrhythmics, antioxicants,anti-asthma agents, hormonal agents including contraceptives,sympathomimetics, diuretics, lipid regulating agents, antiandrogenicagents, antiparasitics, anticoagulants, neoplastics, antineoplastics,hypoglycemics, nutritional agents and supplements, growth supplements,antienteritis agents, vaccines, antibodies, diagnostic agents, andcontrasting agents. The active agent, when administered by inhalation,may act locally or systemically.

The active agent may fall into one of a number of structural classes,including but not limited to small molecules, peptides, polypeptides,proteins, polysaccharides, steroids, proteins capable of elicitingphysiological effects, nucleotides, oligonucleotides, polynucleotides,fats, electrolytes, and the like.

Examples of active agents suitable for use in this invention include butare not limited to one or more of calcitonin, amphotericin B,erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme,cyclosporin, granulocyte colony stimulating factor (GCSF),thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcatonin,granulocyte macrophage colony stimulating factor (GMCSF), growthhormone, human growth hormone (HGH), growth hormone releasing hormone(GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha,interferon beta, interferon gamma, interleukin-1 receptor,interleukin-2, interleukin-1 receptor antagonist, interleukin-3,interleukin-4, interleukin-6, luteinizing hormone releasing hormone(LHRH), factor IX, insulin, pro-insulin, insulin analogues (e.g.,mono-acylated insulin as described in U.S. Pat. No. 5,922,675, which isincorporated herein by reference in its entirety), amylin, C-peptide,somatostatin, somatostatin analogs including octreotide, vasopressin,follicle stimulating hormone (FSH), insulin-like growth factor (IGF),insulintropin, macrophage colony stimulating factor (M-CSF), nervegrowth factor (NGF), tissue growth factors, keratinocyte growth factor(KGF), glial growth factor (GGF), tumor necrosis factor (TNF),endothelial growth factors, parathyroid hormone (PTH), glucagon-likepeptide thymosin alpha 1, IIb/IIIa inhibitor, alpha-1 antitrypsin,phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosphonates,respiratory syncytial virus antibody, cystic fibrosis transmembraneregulator (CFTR) gene, deoxyreibonuclease (Dnase),bactericidal/permeability increasing protein (BPI), anti-CMV antibody, 13-cis retinoic acid, oleandomycin, troleandomycin, roxithromycin,clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin,josamycin, spiromycin, midecamycin, leucomycin, miocamycin, rokitamycin,andazithromycin, and swinolide A; fluoroquinolones such asciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin,moxifloxicin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin,lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin,fleroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin,clinafloxacin, and sitafloxacin, teicoplanin, rampolanin, mideplanin,colistin, daptomycin, gramicidin, colistimethate, polymixins such aspolymixin B, capreomycin, bacitracin, penems; penicillins includingpenicillinase-sensitive agents like penicillin G, penicillin V,penicillinase-resistant agents like methicillin, oxacillin, cloxacillin,dicloxacillin, floxacillin, nafcillin; gram negative microorganismactive agents like ampicillin, amoxicillin, and hetacillin, cillin, andgalampicillin; antipseudomonal penicillins like carbenicillin,ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporinslike cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone,cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin,cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil,cephaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine,cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan,cefinetazole, ceftazidime, loracarbef, and moxalactam, monobactams likeaztreonam; and carbapenems such as imipenem, meropenem, pentamidineisethiouate, lidocaine, metaproterenol sulfate, beclomethasonediprepionate, triamcinolone acetamide, budesonide acetonide,fluticasone, ipratropium bromide, flunisolide, cromolyn sodium,ergotamine tartrate and where applicable, analogues, agonists,antagonists, inhibitors, and pharmaceutically acceptable salt forms ofthe above. In reference to peptides and proteins, the invention isintended to encompass synthetic, native, glycosylated, unglycosylated,pegylated forms, and biologically active fragments, derivatives, andanalogs thereof.

Active agents for use in the invention further include nucleic acids, asbare nucleic acid molecules, vectors, associated viral particles,plasmid DNA or RNA or other nucleic acid constructions of a typesuitable for transfection or transformation of cells, i.e., suitable forgene therapy including antisense. Further, an active agent may compriselive attenuated or killed viruses suitable for use as vaccines. Otheruseful drugs include those listed within the Physician's Desk Reference(most recent edition), which is incorporated herein by reference in itsentirety.

The amount of antibiotic or other active agent in the pharmaceuticalformulation will be that amount necessary to deliver a therapeuticallyor prophylactically effective amount of the active agent per unit doseto achieve the desired result. In practice, this will vary widelydepending upon the particular agent, its activity, the severity of thecondition to be treated, the patient population, dosing requirements,and the desired therapeutic effect. The composition will generallycontain anywhere from about 1 wt % to about 99 wt %, such as from about2 wt % to about 95 wt %, or from about 5 wt % to 85 wt %, of the activeagent, and will also depend upon the relative amounts of additivescontained in the composition. The compositions of the invention areparticularly useful for active agents that are delivered in doses offrom 0.001 mg/day to 100 mg/day, such as in doses from 0.01 mg/day to 75mg/day, or in doses from 0.10 mg/day to 50 mg/day. It is to beunderstood that more than one active agent may be incorporated into theformulations described herein and that the use of the term “agent” in noway excludes the use of two or more such agents.

Generally, the compositions are free of excessive excipients. In one ormore embodiments, the aqueous composition consists essentially of theanti-gram-negative antibiotic, such as amikacin, or gentamicin or both,and/or salts thereof and water.

Further, in one or more embodiments, the aqueous composition ispreservative-free. In this regard, the aqueous composition may bemethylparaben-free and/or propylparaben-free. Still further, the aqueouscomposition may be saline-free.

In one or more embodiments, the compositions comprise an anti-infectiveand an excipient. The compositions may comprise a pharmaceuticallyacceptable excipient or carrier which may be taken into the lungs withno significant adverse toxicological effects to the subject, andparticularly to the lungs of the subject. In addition to the activeagent, a pharmaceutical formulation may optionally include one or morepharmaceutical excipients which are suitable for pulmonaryadministration. These excipients, if present, are generally present inthe composition in amounts sufficient to perform their intendedfunction, such as stability, surface modification, enhancingeffectiveness or delivery of the composition or the like. Thus ifpresent, excipient may range from about 0.01 wt % to about 95 wt %, suchas from about 0.5 wt % to about 80 wt %, from about 1 wt % to about 60wt %. Preferably, such excipients will, in part, serve to furtherimprove the features of the active agent composition, for example byproviding more efficient and reproducible delivery of the active agentand/or facilitating manufacturing. One or more excipients may also beprovided to serve as bulking agents when it is desired to reduce theconcentration of active agent in the formulation.

For instance, the compositions may include one or more osmolalityadjuster, such as sodium chloride. For instance, sodium chloride may beadded to solutions of vancomycin hydrochloride to adjust the osmolalityof the solution. In one or more embodiments, an aqueous compositionconsists essentially of the anti-gram-positive antibiotic, such asvancomycin hydrochloride, the osmolality adjuster, and water.

Pharmaceutical excipients and additives useful in the presentpharmaceutical formulation include but are not limited to amino acids,peptides, proteins, non-biological polymers, biological polymers,carbohydrates, such as sugars, derivatized sugars such as alditols,aldonic acids, esterified sugars, and sugar polymers, which may bepresent singly or in combination.

Exemplary protein excipients include albumins such as human serumalbumin (HSA), recombinant human albumin (rHA), gelatin, casein,hemoglobin, and the like. Suitable amino acids (outside of thedileucyl-peptides of the invention), which may also function in abuffering capacity, include alanine, glycine, arginine, betaine,histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine,isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine,tryptophan, and the like. Preferred are amino acids and polypeptidesthat function as dispersing agents. Amino acids falling into thiscategory include hydrophobic amino acids such as leucine, valine,isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine,histidine, and proline.

Carbohydrate excipients suitable for use in the invention include, forexample, monosaccharides such as fructose, maltose, galactose, glucose,D-mannose, sorbose, and the like; disaccharides, such as lactose,sucrose, trehalose, cellobiose, and the like; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, starches, and the like;and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitolsorbitol (glucitol), pyranosyl sorbitol, myoinositol and the like.

The pharmaceutical formulation may also comprise a buffer or a pHadjusting agent, typically a salt prepared from an organic acid or base.Representative buffers comprise organic acid salts of citric acid,ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinicacid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride,or phosphate buffers.

The pharmaceutical formulation may also include polymericexcipients/additives, e.g., polyvinylpyrrolidones, celluloses andderivatized celluloses such as hydroxymethylcellulose,hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (apolymeric sugar), hydroxyethylstarch, dextrates (e.g., cyclodextrins,such as 2-hydroxypropyl-.beta.-cyclodextrin andsulfobutylether-.beta.-cyclodextrin), polyethylene glycols, and pectin.

The pharmaceutical formulation may further include flavoring agents,taste-masking agents, inorganic salts (for example sodium chloride),antimicrobial agents (for example benzalkonium chloride), sweeteners,antioxidants, antistatic agents, surfactants (for example polysorbatessuch as “TWEEN 20” and “TWEEN 80”), sorbitan esters, lipids (for examplephospholipids such as lecithin and other phosphatidylcholines,phosphatidylethanolamines), fatty acids and fatty esters, steroids (forexample cholesterol), and chelating agents (for example EDTA, zinc andother such suitable cations). Other pharmaceutical excipients and/oradditives suitable for use in the compositions according to theinvention are listed in “Remington: The Science & Practice of Pharmacy”,19.sup.th ed., Williams & Williams, (1995), and in the “Physician's DeskReference”, 52.sup.nd ed., Medical Economics, Montvale, N.J. (1998),both of which are incorporated herein by reference in their entireties.

It should be noted that the methods, systems, and devices discussedabove are intended merely to be examples. It must be stressed thatvarious embodiments may omit, substitute, or add various procedures orcomponents as appropriate. For instance, it should be appreciated that,in alternative embodiments, the methods may be performed in an orderdifferent from that described, and that various steps may be added,omitted, or combined. Also, features described with respect to certainembodiments may be combined in various other embodiments. Differentaspects and elements of the embodiments may be combined in a similarmanner. Also, it should be emphasized that technology evolves and, thus,many of the elements are examples and should not be interpreted to limitthe scope of the invention.

Specific details are given in the description to provide a thoroughunderstanding of the embodiments. However, it will be understood by oneof ordinary skill in the art that the embodiments may be practicedwithout these specific details. For example, well-known processes,algorithms, structures, and techniques have been shown withoutunnecessary detail in order to avoid obscuring the embodiments. Thisdescription provides example embodiments only, and is not intended tolimit the scope, applicability, or configuration of the invention.Rather, the preceding description of the embodiments will provide thoseskilled in the art with an enabling description for implementingembodiments of the invention. Various changes may be made in thefunction and arrangement of elements without departing from the spiritand scope of the invention.

Further, the preceding description generally details aerosolizing liquiddrugs. However, it should be understood that liquids besides liquiddrugs may be aerosolized using similar devices and methods.

Also, it is noted that the embodiments may be described as a processwhich is depicted as a flow diagram or block diagram. Although each maydescribe the operations as a sequential process, many of the operationscan be performed in parallel or concurrently. In addition, the order ofthe operations may be rearranged. A process may have additional stepsnot included in the figure.

1. (canceled)
 2. A method for operating a nebulizer, the methodcomprising: driving an element of the nebulizer using an electricalsignal to cause the element to atomize a liquid; measuring a phase shiftbetween a voltage and a current of the electrical signal that drives theelement of the nebulizer; based at least in part on the measured phaseshift of the electrical signal, determining a frequency at which todrive the element of the nebulizer; calculating a voltage magnitude forthe electrical signal based on the determined frequency, wherein thecalculated voltage magnitude is used to maintain consistent dropletsizing of the liquid being atomized; and causing the electrical signaldriving the element of the nebulizer to have the calculated voltagemagnitude and the determined frequency.
 3. The method for operating thenebulizer of claim 2, wherein calculating the voltage magnitude for theelectrical signal is further based on a type of the liquid beingatomized.
 4. The method for operating the nebulizer of claim 2, furthercomprising: adjusting the frequency of the electrical signal to maintaina substantially constant phase shift between the voltage and current ofthe electrical signal.
 5. The method for operating the nebulizer ofclaim 2, wherein a reservoir that stores liquid to be atomized by theelement causes a resonant frequency to vary as the liquid is drainedfrom the reservoir.
 6. The method for operating the nebulizer of claim5, further comprising: draining the liquid from the liquid reservoir tosupply the element of nebulizer with the liquid, wherein the liquidreservoir is sealed to allow a pressure within the liquid reservoir todecrease as the liquid is drained.
 7. A system for driving an element ofa nebulizer, the system comprising: an amplifier that generates anoutput waveform signal, the output waveform signal comprising an outputfrequency, an output current, and an output voltage, wherein the outputwaveform signal drives the element of the nebulizer at the outputfrequency; a phase shift detector component that measures a phase shiftbetween the output current and the output voltage of the output waveformsignal; a frequency tracker component that generates a waveform signalof a variable frequency that is input to the amplifier, wherein thewaveform signal controls the output frequency and the variable frequencyis adjusted based on the phase shift of the output waveform signalmeasured by the phase shift detector component; and a voltage profilecomponent that controls a magnitude of the output voltage of the outputwaveform signal based on the frequency of the waveform signal generatedby the frequency tracker wherein the magnitude of the output voltage isused to maintain consistent droplet sizing of the liquid being atomized.8. The system for driving the element of the nebulizer of claim 7,wherein the voltage profile component that controls the magnitude of theoutput voltage of the output waveform signal further controls themagnitude of the output voltage based on a type of liquid beingatomized.
 9. The system for driving the element of the nebulizer ofclaim 7, wherein the voltage profile component calculates the magnitudebased on the frequency of the waveform signal generated by the frequencytracker.
 10. The system for driving the element of the nebulizer ofclaim 7, the system further comprising a liquid reservoir that causes aresonant frequency of the element of the nebulizer to vary as liquid isdrained from the liquid reservoir.
 11. The system for driving theelement of the nebulizer of claim 10, wherein the liquid reservoir isconfigured to be sealed such that a negative pressure, as compared to anexternal environment, develops as the liquid is drained from the sealedliquid reservoir for atomization by the element of the nebulizer. 12.The system for driving the element of the nebulizer of claim 7, whereinthe driver device is coupled with the nebulizer as part of a handheldunit.
 13. The system for driving the element of the nebulizer of claim7, wherein the frequency tracker component adjusts the frequency of theoutput waveform signal to maintain a substantially constant phase shiftbetween the voltage and current of the output waveform signal.
 14. Asystem for atomizing a liquid, the system comprising: a liquid reservoirfor holding the liquid that is to be atomized; a nebulizer comprising anelement having a plurality of apertures, wherein: the element isconfigured to vibrate to atomize the liquid drained from the liquidreservoir wherein the element is driven by an output waveform signal;and a pressure within the liquid reservoir changes as liquid stored inthe liquid reservoir is drained and atomized by the element; and adriver unit, comprising: a phase shift detector component for measuringa phase shift between a current of the output waveform signal and avoltage of the output waveform signal; a frequency tracker componentthat generates a waveform that adjusts the frequency of the outputwaveform signal, wherein the frequency is adjusted based on the phaseshift determined by the phase shift detector component; and a voltageprofile component that controls a magnitude of the voltage of the outputwaveform signal based on the frequency of the waveform generated by thefrequency tracker component wherein the magnitude of the voltage is usedto maintain consistent droplet sizing of the liquid being atomized. 15.The system of atomizing liquid of claim 14, wherein the voltage profilecomponent that controls the magnitude of the voltage of the outputwaveform signal further bases the magnitude on a type of liquid beingatomized.
 16. The system of atomizing liquid of claim 14, wherein thevoltage profile component calculates the magnitude based on thefrequency of the waveform generated by the frequency tracker component.17. The system for atomizing liquid of claim 14, wherein the liquidreservoir is configured to be sealed with the liquid inside such that apressure within the liquid reservoir decreases when the liquid isdrained for atomization.
 18. The system of atomizing liquid of claim 14,wherein the driver is coupled with the nebulizer in a handheld unit. 19.The system of atomizing liquid of claim 14, wherein the driver furthercomprises an amplifier configured to generate the output electricalsignal using signals from the frequency tracker component and thevoltage profile component.
 20. The system of atomizing liquid of claim14, wherein a processing unit of the driver unit is configured tocompare the measured phase shift with a desired phase setpoint todetermine a phase error value.
 21. The system of atomizing liquid ofclaim 20, wherein the processing unit of the driver unit is furtherconfigured to, based on the determined phase error value, store anindication of a current frequency being output by the frequency trackercomponent.